Carpal tunnel syndrome (CTS) is one of the most common causes of work-related disability in the US. The most common pathological finding is non-inflammatory synovial fibrosis and thickening, but whether this fibrosis is a cause of, or merely an associated finding with the compression neuropathy of the median nerve that is characteristic of CTS is unknown. This study will attempt to address this important issue by investigating the motion behavior, mechanical properties, and biological response of the synovium, and specifically the subsynovial connective tissue (SSCT), the gliding interface which links the tendons and synovium in the carpal tunnel. We hypothesize that activity-related damage may occur to the SSCT, resulting in fibrosis, diminished elasticity and increased gliding resistance in the carpal tunnel, setting up a vicious cycle of progressive injury that ultimately impairs permeability of the synovium, increases carpal tunnel pressure, and thereby causes the median neuropathy of CTS. To test this hypothesis, we propose three Specific Aims. Aim 1 is to describe the motion characteristics of the SSCT, by video, fluoroscopic, and ultrasound imaging, in normal human cadavers, patients with CTS, and in candidate animal models of CTS (dog and rabbit); in Aim 2, the mechanical properties and permeability of the SSCT in these same groups will be studied and compared. Aim 3 will characterize the histology and immunohistochemistry of the SSCT in these tissues; if this hypothesis regarding the etiology of CTS is correct, a biological basis for cumulative trauma as an etiology will be established for the first time for CTS. In addition, suitable animal models will be characterized for further experimental investigations of CTS. Finally, a new perspective would be provided, which could serve as a foundation for new therapies and prevention strategies for CTS. [unreadable] [unreadable]